Steroids of the 19-norpregnane series



Unite 3,077,471 STEROIDS F Tl-m 19-NORPREGNANE SERIES Josef Fried, Princeton, and Mariano A. Guiducci, Edison,

N.J., assignors to Olin Mathieson Chemical Corporation, New York, N.Y., a corporation of Virginia N0 Drawing. Filed Aug. 4, 1961, Ser. No. 129,233 13 Claims. Jl. zen-239.55

wherein R is in either the alpha or beta position and represents hydrogen or lower alkyl; R is hydrogen or lower alkyl (preferably methy); R is hydroxy or acyloxy (preferably the acyloxy radical of a hydrocarbon carboxylic acid of less than ten carbon atoms); R is hydrogen; or together R and R' is 0x0 (0:); P is hydrogen, lower alkyl, halo lower alkyl, monocyclic cycloalkyl, monocyclic cycloalkyl lower alkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclic or monocyclic heterocyclic lower alkyl; Q is lower alkyl, halo lower alkyl, monocyclic cycloalkyl, monocyclic cycloalkyl lower alkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclic heterocyclic or monocyclic heterocyclic lower alkyl; or together with the carbon to which they are joined P and Q is a monocyclic cycloalkyl or monocyclic heterocyclic radical.

The final products of this invention are physiologicallyactive substances which possess estrongenic activitiy when administered both in the form of tablets and as a solution or suspension and hence can be used in lieu of known estrogenic agents, such as estrone or estradiol benzoate in the treatment of menopausal symptoms. For this purpose, they can be administered in the same manner as estrone or ,estadiol benzoate, for example, the dosage being adjusted for the relative potency of the particular steroid.

Those compounds of this invention wherein P is hydrogen, lower alkyl, halo lower alkyl, monocyclic cycloalkyl, or monocyclic cycloalkyl lower alkyl, Q is lower alkyl, halo lower alkyl, monocyclic cycloalkyl or monocyclic cycloalkyl lower alkyl, or together with the carbon to which they are joined P and Q is monocyclic cycloalkyl, are also useful as intermediates in the preparation 19-nor- 160:,17 a dihydroxyprogesterone, 19-nor-5( l0)-pregnene- 16a,17a-diol-3,20-dione, or acetal or ketal derivatives States Patent r EQQ thereof, as more fully described in our application, Serial No. 129,234, filed on even date herewith.

The compounds of this invention can be prepared by pyrolyzing a compound of the Formula II (H) CH3 wherein R' (in either the alpha or beta position), P and Q are as hereinbefore defined.

The pyrolysis is preferably conducted by heating the steroid reactant to a temperature above about 400 C., preferably about 500 C. to about 700 C., and results in the preparation of the 3-hydroxy-20-keto final products of this invention of the Formula III wherein R, P and Q are as hereinbefore defined.

The S-hydroxy-ZO-keto products can then be etherifiecl by treatment with a lower alkyl halide or sulfate (e.g., dimethyl sulfate, dicthyl sulfate, propyl chloride, n-butyl chloride, and n-hexyl chloride), in the presence of a base, such as potassium hydroxide, to yield the corresponding 3-ether derivatives of the Formula IV wherein R, R, P. and Q are as hereinbefore defined, which are new compounds of this invention.

The resulting 3-ether-20-keto steroids can then be reduced, as by treatment with lithium aluminum hydride or 3% sodium borohydride to yield the corresponding ZOtt-hydroxy derivatives of the Formula V wherein R, R, P and Q are as hereinbefore defined, which are also new compounds of this invention; and these 205- hydroxy compounds can then be esterified in the usual manner by treatment with an acid anhydride or acyl halide, preferably in the presence of a basic catalyst, such as pyridine, to yield products of this invention of the Formula VI (VI) CH3 wherein R, R, P and Q are as hereinbefore defined and Y is an acyl radical, preferably the acyl radical of a hydrocarbon carboxylic acid of less than ten carbon atoms, as exemplified by the lower alkanoic acids (e.g., acetic, propionic, butyric and enanthic acid), lower alkenoic acids, monocyclic aryl carboxylic acids (e.g., benzoic and m-toluic acid), monocyclic aryl lower alkanoic acids (e.g., phenacetic and B-phenylpropionic acid), monocyclic aryl lower alkenoic acids, cycloalkanecarboxylic acids, and cycloalkenecarboxylic acids.

The 16,17-acetal and ketal derivatives, and especially the acetals and ketals with aromatic aldehydes and ketones, can also be prepared by hydrolyzing compounds of the Formulae III or IV to yield new intermediates of this invention of the Formula VII (VII) CH3 wherein R is as hereinbefore defined and R" is hydrogen or lower alkyl. This hydrolysis is accomplished by treating the steroid with formic acid. If concentrated aqueous formic acid is used (e.g., 90% formic acid), a 16-formic acid ester or, if R" is hydrogen, a 3,16-diester is formed initially, which is then hydrolyzed by treatment with aqueous potassium carbonate in methanol to yield the free 16,17 -dihydroxy steroid derivative.

45 These free 16,17-dihydroxy steroids can then be reacted with an aldehyde or ketone of the formula:

wherein P and Q are as hereinbefore defined, to give the final acetal and ketal derivatives of this invention.

In those instances where the starting steroids are new compounds, they can be prepared by reacting a compound of the formula wherein R, P and Q are as hereinbefore defined, with 2,3- dichloro-S,6-dicyanobenzoquinone, whereby a doublebond is introduced between the 1 and 2 positions, thereby yielding the starting steroids of this invention. The reaction is preferably conducted in an organic solvent for the steroid reactant at an elevated temperature, preferably the refiux temperature of the solvent. These steroids may also be prepared by microbiological dehydrogenation using an organism such as C. simplex or B. cyclooxidarzs.

If a ketal or acetal grouping other than that present in the starting steroid reactant is desired, the resulting product may be cleaved by treatment with aqueous formic acid to yield 16a,17a-dihydroxy intermediates of the formula.

wherein R is as hereinbefore defined. If concentrated aqueous formic acid is used (e.g., formic acid), a 16-formic acid ester is formed, which is then hydrolyzed by treatment with 10% aqueous potassium carbonate in methanol to yield the free 16,l7-dihydroxy steroid derivative.

These intermediates are than reacted with an aldehyde or ketone of the formula:

'ainidooenzaldehydes as acetone, diethyllcetone, dibutylketone, methylethylketone, and methylisobutylketone; cycloalkanones, such as cyclobutanone, cyclopetanone, cyclohexanone, suberone, and cyclodexanone; cycloalkyl (lower alkanals), such as cyclopropylcarboxaldehyde, cyclobutylcarboxyaldehyde, cyclopentylcarboxaldehyde, cyclohexylcarboxaldehyde, cycloheptylcarboxaldehyde, cyclooctylcarboxaldehyde, cyclopropylacetaldehyde, cyclobutylacetaldehyde, cyclopentylacetaldehyde, cyclohexylacetaldehyde, fi-cyclopentylpropionaldehyde, y-cyclohexylbutyraldehyde, and 3-cyclopropylcaproaldehyde; cycloalkylflower alkanones), such as cyclopropyl methyl ketone, cyclobutyl ethyl ketone, cyclopentyl propyl ketone, cyclopentylmethyl methyl ketone, cyclohexylmethyl ethyl ketone, cyclopentylethyl ethyl ketone, cyclopropylpropyl methyl ketone, cyclohexyl n-penyl ketone, cyclohexyl methyl ketone, and cyclooctyl methyl ketone; dicycloalkyl ketones, such as dicyclopropyl ketone, dicyclobutyl ketone, dicyclopentyl lcetone, dicyclohexyl lretone, cyclopentyl cyclohexyl ketone, cyclopropylmethyl cyclopropyl ketone, 2-cyclobutylethyl cyclopropyl ketone, B-cycIopentylmethyl cyclopentyl ketone, S-cyclohexylhexyl cyclohexyl ketone, di- (cyclopentylmethyl) ketone, cyclohexylmethyl cyclopentyl ketone, and di(4-cyclohexylpentyl) ketone; cycloalkyl monocyclic aromatic ketones, such as cyclopropyl phenyl ketone, cyclohexyl p-chlorophenyl ketone, cyclopentyl omethoXyphenyl ketone, cyclopentyl o,p-dihydroxyphenyl ketone, cyclohexyl m-tolyl ketone, cyclopropyl p-ethylphenyl ketone, cyclopropyl p-nitrophenyl ketone, and cyclohexyl p-actamidophenyl ketone; cycloalkyl(lower alkyl) monocyclic aromatic ketones, such as cyclopentylmethyl phenyl ketone; cycloalkyl monocyclic aromatic lower alkyl) kctones, such as cyclopentyl benzyl ketone, cyclohexyl phenethyl ketone, and cyclobutyl benzyl ketone; cycloalkylflower alkyl) monocyclic aromatic (lower alkyl) ketones, such as cyclopentylmethyl benzyl ketones; cycloalkyl monocyclic heterocyclic ketones, such as cyclopentyl Z-furyl ketone, cycloheXyl Z-thienyl ketone, and cyclopropyl 2-pyridinyl ketone; cycloalkyl (lower alkyl) monocyclic heterocyclic ketones, such as cyclopentylmethyl 2-piperidinyl ketone, cyclohexylethyl 2-morpholinyl ketone and cyclopropyl Z-thienyl ketone; cycloalkyl monocyclic heterocyclic (lower alkyl) ketones, such as cyclopentyl thenyl ketone, cyclohexyl furfuryl ketone and cyclopropyl 2-piperidinylmethyl ketone; halo-lower alkanals, such as chloral hydrate, triiluoroacetaldehyde hemiacetal, and heptafiuorobutanal ethyl hemiacetal; halolower alkanones, such as 1,1,l-trifiuoroacetone; monocyclic carbocyclic aromatic aldehydes such as benzaldehyde, halobenzaldehydes (e.g., p-chlorobenzaldehyde and p-fluorobenzaldehyde), lower alkoxybenzaldehydes (e.g., o-anisaldehyde), di(l.ower alkoxy)benzaldehydes (e.g. veratraldehyde), hydroxybenzaldehydes (e.g., salicylalclehyde), dihydroxybenzaldehydes (e.g. resorcyaldehyde), lower alkyl benzaldehydes (e.g. m-tolualdehyde and pethylbenzaldehydeL di(lower alkyDbenZaldehydes (e.g.

o,p-dimethylbenzaldenyde), nitrobenzaldehydes, acyl- -(e.g. N-acetylanthranilaldehyde), and cyanobenzaldehydes; monocyclic carboxylic aromatic lower alkanals, such as phenylacetaldehyde, a-phenylpropionaldehyde, fl-phenylpropionaldehyde, 'y-phenylbutyraldehyde, and aromatically-substituted halo lower alkoxy, hydroxy, lower allcyl, nitro, acylamido and cyano derivatives thereof; monocyclic heterocyclic aldehydes, such as picolinaldehydes, furfural, thiophene carbonals, and halo, lower alkoxy, hydroxy, lower alkyl, nitro, and cyano de rivatives thereof; monocyclic heterocyclic lower alkanals; monocyclic carbocyclic aromatic ketones, such as acetophenone, a,a,a-trifiuoroacetophenone, propiophenone, butyrophenone, valerophenone, isocaprophenone halophenyl lower alkyl ketones (eg. p-chloroacetophenot1e and p-chloropropiophenone), (lower alkoxy) phenyl lower alkyl ketones (eg. p-anisyl methyl ketone), di(lower alkoxy)phenyl lower alkyl ketones, hydroxy-phenyl lower alkyl ketones, dihydroxyphenyl lower alkyl ketones (e.g. resacetophenone), (lower alkyl) phenyl lower alkyl ketones (eg. methyl p-tolyl ketone), di(lower alkyl)- phenyl lower alkyl ketones (o,p-xylyl methyl ketone); nitrophenyl lower alkyl ketones (e.g. p-nitroacetophenone), acylamidophenyl lower alkyl ketones (e.g. acetyl anilines), and cyanophenyl lower alkyl ketones; benzophenone, and mono or his substituted halo, lower alkoxy, hydroxy, lower alkyl, nitro, acylamido and cyano derivatives thereof; monocyclic carbocyclic aromatic lower alkanones, such as 1-phenyl-3-butanone and l-phenyl-4- pentanone, and aromatically substituted derivatives thereof; monocyclic heterocyclic ketones, such as 2-acety1furan, 2-benzoylfuran, Z-acetyl-thiophene and alloxan; and monocyclic heterocyclic lower alkanones.

Among the suitable initial steroid reactants may be mentioned the 16,17-acetals and ketals of each of the following steroids with one of the aldehydes or ketones listed hereinbefore: 16a,l7a-dihydroxy-l-clehydro-progesterone, and 6-(lower alkyl)46a,17u-dihydroxy-1-dehydroprogesterones, such as 6a-methyl-16a,17a-dihydroxy-l-dehydroprogesterone, 6,6-methyl-16a,l7a-dihydroxy-l-dehydroprogesterone and a-ethyl-16u,17a-dihydroxy-1-dehydroprogesterone.

The following examples illustrate the preparation of suitable starting steroids useful in the process of this invention (all temperatures being in centigrade):

EXAMPLE A 1 -Dehydro-1 6 0a,] 7 a-Dihydroxy progesterone 1 604,] 7 d- Acetonide EXAMPLE B .1-Dehydr0-16J 701-1)ihydroxyprogesterone 1604,17- Acetophenoniae Following exactly the procedure of Example A but substituting 16a,17a-dihydroXyprogesterone acetophenonide for the acetonide, l-dehydro-l6a,l7u-dihydroxyprogesterone 16u,l7a-acetophenonide is formed. Recrystallization from ether-hexane furnishes the pure product.

EXAMPLE C :,17a-Chl0h1l Derivative of A -Pregnadiene-Ma,

1 7a-Diol-3,20-Dione Followingthe procedure of Example A but substituting an equivalent amount of the l6cz,17a-Chl( fal derivative of 16a,l7a-dihydroxyprogesterone for the 16,l7a-dihydroxyprogesterone 16,17-acetonide, the 116:2,l7oc-Chl0l3l derivative of A -pregnadiene-16tz,l7a-diol-3,20-dione is obtained.

EXAMPLE D Dicyclopropyl Ketone Derivative of A -Pregnadiene- 16ot-17et-Di0l-3,20-Di0ne Following the procedure of Example A but substituting an equivalent amount of the l6a,17a-dicyclopropyl keton derivative of 160:,17a dihydroxyprogesterone for the 16a,17u-dihydroxyprogesterone 16,17-acetonide, the. di-

EXAMPLE E 60L-M ethyl-1 -Dehydr-1 6 (1,1 7a-D ihydroxyprogesterone .16a,17a-Acet0nide A solution of 12.5 g. of 6a-methyl-16a,17u-dihydroxyprogesterone 16u,17ot-acet0nide and 8.7 g. of 2,3-dichloro- 5,6-dicyanobenzoquinone in 100 ml. of anhydrous dioxane is refluxed for hours. The cooled reaction mixture is filtered and washed several times with 5 ml. portions of dioxane, and the solvent removed in vacuo. The crude material is then chromatographed as in Example A to yield the l-dehydro product.

EXAMPLE F 6fi-Methyl-1-Dehydro-1 6a,] 7a-Dihydroxyprogesterone 1 6a,] 7u-A cetom'de Following the procedure of Example E but substituting an equivalent amount of 6fl-methyl-16a,17ot-dihydr0xyprogesterone 16,17-acetonide for the 6a-methyl-16a,17udihydroxyprogesterone 16,17-acetonide, 6fl-methyl-A pregnadiene-l6a,17a-diol-3,20-dione 16,17 -acetonide is obtained.

EXAMPLE G 6 a-M ethyl-A -Pregnadien e-] 6 ,1 7 a-Diol-3,20-Di0ne 16,1 7 -A cetoph enonide A Following the procedure of Example E but substituting an equivalent amount of oa-methyl-l6u,17a-dihydroxy progesterone 16,17-acetophenonide for the oer-methyl- 16a,17u dihydroxyprogcsterone 16,17 acetonide, 6ozmethyl-A -pregnadiene-160;,17ct-di01 3,20 dione 16,17- .acetophenonide is obtained.

EXAMPLE H A -Pregnadiene-IGuJ 7a-Diol-3,20-Dione A solution of 900 mg. of A -pregnadiene-loa,17a-diol- 3,20-dione 16,17-acetonide in ml. of 90% formic acid is heated at 42 for 22 hours. The solvents are removed in vacuo, the crude residue dissolved in 50 ml. of methanol and treated under nitrogen with stirring with 10 ml. of a 10% oxygen-free solution of potassium carbonate in Water. After 13 minutes at room temperature the mixture is neutralized with 1 ml. of glacial acetic acid and the solution concentrated in vacuo after the addition of water. Extraction with chloroform followed by drying over sodium sulfate and evaporation in vacuo furnishes a residue which on recrystallization from 95% ethanol furnishes about 200 mg. of pure A -pregnadiene-160:,17adiol-3,20-dione.

EXAMPLE I 6a-M ethyl-A -Pregnadiene-I 6 04,1 7a-Di0l-3,20-Dione Following the procedure of Example H, but substituting an equivalent amount of fia-methyl-A -pregnadiene- '16,17a-'diol-3,'20-dione 16,17-acetonide for the A pregnadiene-l6a,17a-diol-3,20-dione 16,17-acetonide, 6amethyl-A -pregnadiene-16a,17ot-diol-3,20-dione is obtained.

Similarly, 6a-methyl-A -pregnadiene 16a,17ot -diol- 3,20-dione 16,17-acetonide yields 6a-methyl-A -pregnadiene 16a,17a-diol-3,20-dione.

EXAMPLE I A -Pregnadi ens-1 604-1 7 a-D i0l3,20-Dione 16,17-Acet0nide To a suspension of 500 mg. of A pregnadiene- 16a,l7cL-diOl-3,20-di0l16 in 75 ml. of acetone is added 0.05 of 72% perchloric acid and the mixture is agitated at room temperature for three hours. The mixture is then neutralized with dilute sodium bicarbonate and the ace-. tone removed in vacuo. The resulting crystalline suspension is filtered and the crystals washed with water to yield, after recrystallization from acetone, A -pregnadiene- 16a,17a-diol-3,20-dione 16,17-acetonide, identical to the product obtained in Example A.

Similarly, the 6-(lower alkyl)-A -pregnadiene-l6a,17adiol-3,20 diones can be converted to their acetonide derivatives. Moreover, by substituting other aldehydes and ketones for the acetone in Example I, the other acetal and ketal starting steroids of this invention can be pre pared.

The following examples illustrate the process of this invention:

- EXAMPLE 1 19-N0r-1,3,5 (1 0 -Pregnatriene-3,I 6 11,1 7 oc-T ri0l-20-0ne 1 6 11,1 7zx-Acetonide A solution of 2 g. of A 460,17a-dihydroxyprogesterone v16 r,17ot-acetonide in'200 ml.- of mineral oil, heated to to maintain solution, is dropped through a glass tube 11 mm. in diameter and 30 cm. long, a 17 cm. length of which is filled with glass helices and heated to 640 in an electric furnace. The rate of addition is adjusted to permit refluxing but not flooding. The temperature of the furnace drops by 30 to 40 when the mineral oil solution passes through the tube thus establishing a pyrolysis temperature of 600610, which is maintained during the experiment. The efiluent solution is diluted with an equal volume of hexane and extracted with 5% alkali. The resulting alkaline extract of crude phenolic compounds is acidified with dilute hydrochloric acid and extracted with chloroform. The chloroform layer is washed with sodium bicarbonate and sodium chloride solutions, dried over sodium sulfate and the solvent removed in vacuo. The crude residue, about 0.9 g., is dissolved in 25 ml. of

benzene and chromatographed on 25 g. of neutral alumina.

Elution of the column with benzene:ether 4:1 (1.5 1.) provides about 220 mg. (10% yield) of 19-nor-1,3,5(10)- pregnatriene-B,l6a,17a-triol 20 one 16a,17ot-acetonide, M.P. about -195. Recrystallization from acetonehexane gives the pure compound of the following properties: M.P. about 203-204"; [a] -]1O2(C., 1.1 in

chlf.

k221i? 2 89, 5.86, 6.15 and 6.30 A31; 281 m (e=2430), shoulder at 286 m (6:2250) minimum at 247 my Analysis.Calcd. for C H O (370): C, 74.56; H, 8.16. Found: C, 74.54; H, 8.39.

EXAMPLE 2 J 9-Nor-I,3,5 (10 )Prcgnatriene-3,I6a,] 7a-Triol-20-0ne 1600,] 7 u-A cetophenonide A solution of 4 g. of the acetophenone derivative of A -16ot,17a-dihydroxyprogesterone in 400 ml. of mineral oil is treated as described in Example 1. To the crude pyrolysis solution is added 400 ml. of hexane, which results in the formation of a precipitate, which is removed by filtration (1.4 g.). The precipitate is dissolved in 50 ml. of benzene and chromatographed on 40g. of neutral alumina. Elution of the column with benzene:ether 5:1 (1 l.) and 1:1 (21.) provides about 250 mg. (6% yield) of the 16a,17a-acetophenone derivative of 19-nor.-l,3, 5 (10) pregnatriene 3,16a,17a-triol-20-one, M.P. about 185-190. Recrystallization from acetone-hexane furnishes analytically pure material having the following properties: M.P. about 193-195"; [a] +46 (c., 1.0 in chlf.);

A231,? 202, 5.85, 0.13, 6.29, 13.05 and 142%; X513; 280 my (e -2370), shoulder at 285 m (e=1980) Analysis.Calcd. for C d-1 (432): C, 77.75; H, 7.46. Found: C, 77.76; H, 7.53.

EXAMPLE 3 1601,17cz-Chl0i'dl Derivative 0f 19-N0i=1,3,5(10)-Pregnametre-3,16a,I7ot-Tri0l-20-One Following the procedure of Example 1 but substituting an equivalent amount of the l6ot,l7u-chloral derivative of o -pregnadiene-la,l7a-diol-3,20-dione for the acetonide, the 160:,17a-Chl0131 derivative of 19-nor-1,3,5(10)- pregnatriene-llfia,17a-triol-20-one is obtained.

EXAMPLE 4 16st,] 7 a-Dicyclopropyl Ketone Derivative of I 9-N0r-1 ,3, -Pregnatriene-3,16a,1 704-1 riol-ZO-One Following the procedure of Example 1 but substituting an equivalent amount of the 16u,17a-dicyclopropyl ketone derivative of h -pregnadiene-loa,17a-diol-3,20- dione for the acetonide, the 16u,17c-dicyclopropyl ketone derivative of 19-nor-1,3,5(10) pregnatriene 3,16ut,170L- triol-ZO-one is obtained.

Similarly, the methylisobutyl ketone derivative, the cyclopropyl phenyl ketone derivative, the cyclohexyl methyl ketone derivative, the 1,1,1-trifiuoroacetonide derivative, the heptafiuorobutanol derivative, the p-chloroacetophenone derivative, the p-nitroacetophenone derivative, the benzaldehyde derivative, the furfural derivative, the benzophenone derivative and the 2-acetylfuran derivative of A -pregnadiene-16a,17w ,20-dione, yield the methylisobutyl ketone, the cyclopropyl phenyl ketone, the cyclohexyl methyl ketone, the 1,1,l-trifiuoroacetonide, the heptafiuorobutanol, the p-chloroacetophenone, the p-nitroacetophenone, the benzaldehyde, the furfural, the hemephenone and the Z-acetylfuran derivatives of 19-n0r-1,3, 5 10)-pregnatriene-3,16a, 17 u-triol-20-one.

EXAMPLE 5 Ga-Methy Z-J 9-N0r-1 ,3 ,5 (1 0) -Pregnatriene-3,1 6 a,1 7 Ot- Triol-ZO-One 1605,1705-14682011 618 Following the procedure of Example 1 but substituting an equivalent amount of 6e-rnethyl-1-dehydro-16ot,17a-

dihydroxyprogesterone l6a,l7 i-acetonide for the A l6a,17ot-dihydroprogesterone 16a,l7a-acetonide, oz-rnethyl-19-nor-1,3,5(10) pregnatriene 3,16a,17wtriol-20-one EXAMPLE 6 6,8-Methyl-19-I f0r-Li5 (10)-Pregnatriene-3,16a,17a- Triol-ZO-One 160t-17oL-A68Z0ilid6 Following the procedure of Example 1 but substituting an equivalent amount or" 6,8-methyl-l-dehydro-ladhdihydroxyprogesterone 16s.,17et-acetonide for the A -16a, l7m-dihydroxyprogesterone 16,l7a-acet0nide, 6/3-methyl- 1-nor 1,3,5(10) pregnatriene 3,160t,17o: triol-ZG-one l6ct,l7u.-acetonide is obtained.

EXAMPLE 7 605-191 ethyl-1 9-N or-I ,3,5 l 0)-Pregitatriene-3,] 6a,] 70:-

Triol-ZU-One 1 601,1 7a-Acetophenonide to EXAMPLE 8 1 9-N0r-3-Meth0xy-1 ,3 ,5 (10) -Pregnatriene-.16a,1 71z-Di0l- ZO-One 1 6a,] 7a-Acet0nide A 5 83, 6.19 and 6.34 A315,, 278 mp (e=2400), 287

Analysis.-Calod. for C H O (384); C, 74.97; H, 8.39; OCH 8.07. Found: C, 74.90; H, 8.22; OCH 7.89.

EXAMPLE 9 19-N0r-3-Methoxy-1 ,3,5 (1 0) -Pregnatriene-16a,1 7 a- ZO-One 1 5a,] 7ot-Acetophenonide A solution of 52 mg. of the 16a,17u-acetophenone derivative of 19-nor-1,3,5(l0)-pregnatriene-3,16a,17a-triol- 3-one in 4 ml. of ethanol is treated with alkali and dirnethyl sulfate as described in Example 8. Crystallization of the crude product from methanol yields about 40 mg. of the acetophenone derivative of l9-nor-3-methoxy-l,3, 5 (10)-pregnatriene-16 x,l7et-di0l-20-one, M.P. about 142- 145, which on recrystallization from chloroform-methanol furnishes analytically pure compound of the following properties: M.P. about 147-449"; [M +41 (c., 1.0 in chlf.);

A232 5.82, 619, 6.30, 12.92 and 14.15,u; hilt- 278 m (e =2150), 287 m (e=l950), minimum at 246 m Analysis.Calcd. for C H O (446); C, 77.99; H, 7.67; OCH 6.94. Found: C, 78.14; H, 7.72; OCHg, 7.02.

EXAMPLE 10 16 x,1 7ot-Chi01'al Derivative of 19-N0r-3-Meth0xy-L3,

5 (10 -Pregnatriene-J 6 0a,] 7 oL-DiOl-Z O-One Following the procedure of Example 8 but substituting an equivalent amount of 1611,170c-Ch10131 derivative of l9-nor-l,3,5 10)-pregnatriene-3,16a,17x-triol-20-one for the acetonide, 16a,17e-chloral derivative of 19-nor-3- methoxy-l,3,5 (10) pregnatriene 16a,l7tx-diol-20-one is obtained. A

EXAMPLE 1 l 16 7 DL-DITCYCZOPI'OPYI Ketone Derivative of Z9-N0r-3- Methoxy-1,3,5(1 0 -Pregnatriene-1 6 (1,1 7 (1-D i0l-20-0ne Following the procedure of Example 8 but substituting an equivalent amount of 16a,1 7a-dicyclopropyl .ketone derivative of 19-nor-1,3,5(10)-pregnatriene-3,l6 x, l7u-triol-20-one for the acetonide, the l6ot,17adicyclopropyl ketone derivative of 19-nor-3-methoxy-1,3,5(10)- pregnatriene-l6a-17a-diol-20-one is obtained.

Similarly, the methylisobutyl ketone derivative, the cyclopropyl phenyl ketone derivative, the cyclohexyl methyl ketone derivative, the 1,1,1-trifluoroacetonide derivative, the heptafiuorobutanal derivative, the p-chloroacetophenone derivative, the p-nitroacetophenone derivative, the benzaldehyde derivative, the furfural derivative, the benzophenone derivative and the 2-acetylfuran derivative of l9-nor l,3,5(l0) pregnatriene-3,16a,17utriol-ZO-one, yield the methylisobutyl ketone, the cyclopropyl phenyl ketone, the cyclohexyl methyl ketone, the i,l,l-trifiuoroacetonide, the heptafiuorobutanal, the pchloroacetophenone, the p-nitroacetophenone, the benzalsprayer];

1 l dehyde, the furfural, the benzophenone and the 2-acetylfuran derivatives of 19-nor-3rnethoxy-l,3,5(l0)-pregnatriene-l6a,17rx-diol-20-one.

EXAMPLE 12 6a-Methyl-19-Nor-3-Methoxy-1 ,3 ,5 (1 O -Pregnatriene- 1604,17oz-Dil-20-Ofl6 16a,]7wAcet0nide Following the procedure of Example 8 but substituting an equivalent amount of 6a-methyl-l9-nor-l,3,5 (10)- pregnatriene 3,16a,17cct1l0l 20 one 16a,17u-acetonide for the acetonide, 6a-methyl-19-nor-3-methoxy-1,3,5 (10)- pregnatriene-16u,17u-diol-20-one 16,17a-acetonide is obtained.

EXAMPLE 13 6/3-Methyl-1 9-Nor-3-Methoxy-1 ,3 ,5 (1 0 -Pregnatriene- 1 6 a,1 7a-Di0l-20-0ne 1 6 ,1 7 a-A celonia'e Following the'procedure of Example 8 but substituting an equivalent amount of 6fl-methyl-l9-nor-l,3,5(10)- pregnatriene-3,16a,17a-triol-20-one 16a,17a-acetonide for the acetonide, 6,6-methyl-l9-nor-3-methoxy-1,3,5(10)- pregnatriene 160:,17oc-di01-20-O118 16oc,17oc-8.C6t0flld6 is obtained.

- EXAMPLE 14 6a-Methyl-19-N0r-3-Methoxy-1,3,5 (10 -Pregnatriene- 16a,]7a-Di0l-20-0ne 16u,17a-Acet0phen0nide Following the procedure of Example 8 but substituting an equivalent amount of 6/3-methyl-19-nor-1,3,5(l0)- pregnatriene-3,16a,17a-triol-20-one 16a,17a-acetophenonide for the acetonide, 6e-methyl-l9-nor-3-methoxy-l,3, )-pregnatriene-16 x,17a-diol-20-one 1611,17 acetophenonide is obtained.

EXAMPLE 15 19-N0r-3-Meth0xy-1,3,5 (10) -Pregnatriene-16a,1 7,20p- Triol 160a,] 7a-Acet0nide crystallized from acetone-hexane yielding about 225 mg.

of product. The ZOyS-hydroxy compound is obtained in two polymorphic modifications, which melt respectively at about 108l10 and about 149-151. The analytically pure sample has the following properties: M.P. about 149-151 (3.; [a] +49 (c., 0.9 in chit);

E1231? 2.60, 2.65, 6.18 and 6.32;; x353, 277 my (e=2040), 287 m (6=1910) Aizalysis.Calcd. for (3 1-1 0., (386): C, 74.57; H,

8.87. Found: C, 74.45; H, 8.52.

EXAMPLE 16 To a solution of 30 mg. of l9-nor-3-methoxy-l,3, 5(10)-pregnatriene-160;,17m-di0l-20 one 16,17a acetonide in 10 ml. of isopropyl alcohol is added 100 mg. of sodium borohydride. The resulting mixture is refluxed for 18 hours, cooled and the excess borohydride decomposed by the addition of water. After concentration in vacuo and dilution with distilled water the reduction product precipitates.

It is removed by filtration, the precipitate washed with water and recrystallized from acetone-hexane.

EXAMPLE 17 19-NOT-3-M6th0xy-I ,3,5 (1 0 Pregnatri ene-1 6 11,] 711,205-

To a solution of 33 mg. of the 160:,17ot-3C6i013h5110116 :derivative 7 of 3-methoxy-19-nor-1,3,5(10)-pregnatriene- 160:,1704-(1101-20-0116 in 15 ml. of tetrahydrofuran is added mg. of lithium borohydride. The mixture is refluxed for 8 hours, cooled and excess borohydride decomposed by the addition of water. After the evaporation of the organic solvent the aqueous solution is extracted with chloroform and the resulting chloroform extract washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness in vacuo. The product, about 40 mg., cannot be induced to crystallize even after column chromatography.

2.80, 5.79 (very weak); 13.05 and 14.20,.

EXAMPLE l8 e,] 7a-Chloral Derivative of 19-N0r-3-Methoxy- 1 ,3,5 (1 0 -Pregnatriene-16a,1 7a,Z0-Tri0l Following the procedure of either Example 15 or Example 16, but substituting an equivalent amount of the 160:,170c-Cl1101fi1 derivative of 19-nor-3-methoxy-1,3,5(10)- pregnatriene-l6a,l7a-diol-20-one for the acetonide, the 16m, l7a-chloral derivative of l9-nor-3-methoxy-l,3,5 l0)- pregnatriene-l6a,17a,20,8-trio1 is obtained.

EXAMPLE 19 16a,17a-Dicyclopropyl Ketone Derivative of 19-N0r-3- Methoxy-1,3,5 (10) -Pregnatriene-16a,17a-Triol Following the procedure of either Example 15 or Example 16, but substituting an equivalent amount of the l6a,17u-dicyclopropyl ketone derivative of l9-nor-3- methoxy-l ,3,5 10)-pregnatriene-16a,17a-diol-20-one for the acetonide, the 16a,17a-dicyclopropyl ketone derivative of 19-nor-3-methoxy- 1,3,5 10) -pregnatriene- 1 6oz, 1711,205- triol is obtained.

Similarly, the methylisobutyl ketone derivative, the cyclopropyl phenyl ketone derivative, the cyclohexyl methyl ketone derivative, the 1,1,1-trofiuoroacetonide derivative, the heptafiuorebutanal derivative, the p-chloroacetophenone derivative, the p-nitroacetophenone derivative, the benzaidehyde derivative, the furfural derivative, the benzophenone derivative and the Z-acetylfuran derivative of l9-nor-3-methoxy-1,3,5 l0)-pregnatriene-l6a,17a-diol- 20-one, yield the respective 16a, 17a-cyclic ketal derivatives of 19-nor-3-methoxy-l,3,5(10)-pregnatriene-16a,17a, 20 3-triol.

EXAMPLE 20 6a-Methyl-1 9-N0r-3-Il4ethoxy-1,3,5 (1 0) -Pregnatriene- 1 6a,] 7 0:,205-1 riol 16a,17a-Acet0nide Following the procedure of either Example 15 or Example 16, but substituting 6a-methyl-19-nor-3-meth0xy- 1,3,5 l 0) -pregnatriene-l 6a, 17oc-di0l-20-0118 16a,17m-acetonide for the acetonide, Got-methyl-l9-nor-3-methoxy-l,3, 5(l0)-pregnatriene-16c,17a,20fi-triol-16a,17u acetonide is obtained. 7

EXAMPLE 21 6,8-Melhyl-J9-Nor-3-Methoxy-1,3,5 (10) -Pregnatriene- 16a,17o:,20,B-Tri0l 1611,] 7a-A cetonide Following the procedure of either Example 15 or Example 16, but substituting 6,8-methyl-19-nor-3-methoxy- 1,3,5 10)-pregnatriene-16a,17o-diol-20-one l6a,17a-acetonide for the acetonide, 6/3-methyl-l9-nor-3-methoxy-1, 3,5 l0) -pregnatriene- 1 6a, 1 7:1,20B-t1i01 1602,17oc-21C6t011id6 is obtained.

EXAMPLE 22 6a-Methyl-1 9-Nor-3-Methoxy-1 ,3,5 1 0 -Pregnatrielze- 16e,17rx, 20,8-Tri0l 16a,17u-Acet0phen0rzide Following the procedure of either Example 15 or Example 16, but substituting a-methyl-l9-nor-3-methoxy- 1,3,5(lO)-pregnatriene-16a,l7a-diol-20-one l6a,l7a acetephenonide for the acetonide, 6a-methyl-l9-nor-3-methoxy-1,3,5(l0)-pregnatriene-16a,17a,20 8-triol 160:,1711- ac-etophenonide is obtained.

13 EXAMPLE 23 19-N0r-3-Meth0xy-1,3,5 (1 -Pre.gnalriene-16a,1 7 a205- Trial 1 611,1 7u-Aceionide 20 8-Acetate A solution of 25 mg. of l9-nor-3-methoxy-1,3,5(10)- pregnatriene-16a,17u,2()fl-triol 16a,17o:-acetonide in 0.5 ml. of acetic anhydride and 0.5 ml. of pyridine is permitted to remain at room temperature for 18 hours. The reagents are then evaporated in vacuo and the residue crystallized from acetone hexane. The pure acetate has the following properties: MP. about 158160;

]n hm? 5.73, 6.20, 6.31, 7.98 and 8.08 1.

EXAMPLE 24 J 9-N0r-3-Methoxy1,3,5 (1 0 -Pregnatriene-16a,1 7 a,20fl-* T riol 1612,17d-AC81OHid8 ZOB-PropiOnate EXAMPLE 2s 19-Nar-1,3,5, )-Pregnatriene-3,16a17a-Tri0l-20-One A solution of 830 mg. of 19 nor-1,3,5(10)-pregnatriene- 3,l6a,17a-triol-20-one 16oz,l7oz-act0l'lide in 25 ml. of 88% formic acid is allowed to remain at 42 for 22 hours. At the end of that period the formic acid is removed completely in vacuo and the residue is dissolved in 83 ml. of oxygen-free methanol. To this solution is added under nitrogen 16.6 ml. of an oxygen-free 10% potassium carbonate solution and the mixture is allowed to remain at room temperature under nitrogen for 30 minutes. 1.7 ml. of glacial acetic acid is then added, followed by 100 ml. of water. Upon removal of the bulk of the methanol in vacuo crystallization of the resulting 19-n0r-1,3,5(10)- pregnatriene-3,16a,17u-triol--one ensues. The crystalline precipitate is filtered, dried and recrystallized from acetone-hexane.

EXAMPLE 26 6a-i /Iethyl-19-N0r-],3,5 (10 )-Pregnatriene-3,16a,1 70:- T ri0l-20-One Following the procedure of Example but substituting an equivalent amount of 6a-methyl-l9-nor-1,3,5(10)- pregnatriene-3,l6a, l7a-triol-20-one l6a,l7oz-acetonide for the acetonide, 6a-methyl-19-nor-1,3,5(10)-pregnatriene-3, 1611,17ct-t1iO1-20-0I16 is obtained.

EXAMPLE 27 6,e-Merhyl-19-Nar-1,3,5 (1 0 -Pregnatriene-3,1 6 0a,] 7a- T riol-20-0ne Following the procedure of Example 25 but substituting an equivalent amount og 6fi-methyl-19-n0r-l,3,5(10)- pregnatriene-3,16a,17a-triol-20-one 16a17a-acetonide for the acetonide, 6fl-methyl-19-nor-1,3,5(10)-pregnatriene-3, l6al7wtriol-20-one is obtained.

EXAMPLE 28 19-Nor-3-Methoxy-1,3,5(I0)-Pregnatriene-16a,17a- Di0l-20-One Following the procedure of Example 25 but substituting an equivalent amount of 19-nor-3-methoxy-l,3',5(1O) i4 pregnatriene-1'6u,17a-diol-20-one l6a,l7a-acetonide for the acetonide, l9-nor-3-methoxy-1,3,5(10)-pregnatriene- 160:,17ez-di0i-20-0I16 is obtained.

EXAMPLE 29 6 a-M ethyl-1 9-N 0r-3-M ethoxy-I ,3,5 (1 0 -Pregnatrien e- 160:,17cc-Di0l-20-0I16 Following the procedure of Example .25 but substituting an equivalent amount of a-methyl-l9-nor-3-methoxyl,3,5 (10)-pregnatriene-16a,17a-diol-20-one 1611,17a-3C3i011id6, for acetonide, 6a-methyl-19-nor-3-meth oxy-1,3,5(10)- pregnatriene-lGa,17u-diol-20-one is obtained.

EXAMPLE 30 6,8-Methyl-1 9-N0r-3-Meth0xy-1,3,5 (10 -Pregnatriene- 160:,17oL-Di0l-20-0H8 Following the procedure of Example 25 but substituting an equivalent amountof 6fi-methyl-l9-nor-3-methoxy-1,3, 5 10) -pregnatriene-16a, 17a-diol-2O-one 160:,17cc-21C6t0t1idfl for the acetonide, 6,8-methyl-19-nor-3-methoxy-1,3,5(10)- pregnatrierie-l6a,17a-diol-20-one is obtained.

EXAMPLE 31 A cetoph enone Derivative of 19-N0r-1,3,5 (10) --Pregnatriene-3,1 6 11,1 7a-Tri0l-20-One A suspension of mg. of 19-nor-l,3,5(10)-pregnatriene-3,16a,l7a-triol-20-one in 5 ml. of redistilled acetophenone and 0.025 ml. of 70% perchloric acid is stirred at room temperature for 1% hours. The resulting solution is neutralized with sodium bicarbonate solution and after the addition of chloroform, the layers are separated and the organic phase washed with water. Removal of the chloroform and acetophenone in high vacuum leaves a residue, which on recrystallization from acetone-hexane gives the pure acetophenone derivative of 19-nor-1,3, 5 l0 -pregnatriene-3,16a,17a-triol-20-one.

EXAMPLE 32 Benzaldehyde Derivatives of 1 9-Nor-1,3,5 (10) -Pregna- Mame-3,1 6 01,1 7 cz-Triol-ZO-One Following the procedure of Example 31 but substituting an equivalent amount of benzaldehyde for the acetophenone, the two isomeric benzaldehyde derivatives of 19 nor 1,3,5(10)-pregnatriene-3,l6a,17u-triol-20-one are obtained, and are separated by chromatographic separation on alumina.

EXAMPLE 33 Furfural Derivatives of 19-N0r-1,3,5(10) -Pregnatriene- 3,1 6 11,1 7e-Tri0l-20-One Following the procedure of Example 31 but substituting an equivalent amount of furfural for the acetophenone, the two isomeric furfural derivatives of l9-nor- 1,3,5(10)-pregnatriene-3,16a,17a-triol-20-one are obtained, and are separated by chromatographic separation on alumina.

EXAMPLE 34 Thiophene-Z-Carboxaldehyde Derivatives of 19-N0r- 1 ,3 ,5 0 -Pregnatriene-3J 6 a,1 7a-Tri0l-20-One Following the procedure of Example 31 but substituting an equivalent amount of thiophene-Z-carboxaldehyde for the acetophenone, the two isomeric thiophene-Z-carboxaldehyde derivatives of 19-nor-1,3,5(10)-pregnatriene- 3,16a,17et-triol-20;one are obtained, and are separated by chromatographic separation on alumina.

15 EXAMPLE 35 EXAMPLE 36 Acetophenone Derivative of 6a-Methyl-19-Nor-1,3,5(10) Pregnatriene-3,I6a,1 7oc-T7'i0l-20-0I1e Following the procedure of Example 31 but substituting an equivalent amount of 9a-methyl-19-nor-1,3,5(l0)- pregnatriene 3,l6oc,l7oz triol-ZO-one for the 19-nor- 1,3",5('10)-pregnatriene-3,16a,17a-triol-20-one, the acetophenone derivative of 6a: methyl 19-nor-l,3,5(10)- pregnatriene-3,1-6a,17a-triol-20-one is obtained.

EXAMPLE 38 iAcetophenone Derivative of 6 8-Methyl19-N0r-1,3,5 (10) Pregnatriene-3,16a,17a-Tril-20-One Following the procedure of Example 31 but substituting an equivalent amount of 6B-methyl-19-nor-1,3,5(10)- pregnatriene-3,16a,l7a triol 20-0ne for the 19-nor- 1,3,5 (l0)-pregnatriene-3,16a,17a-triol-20-one, the acetophenone derivative of 65-rnethyl-19-nor-1,3,5(10)-pregnatriene-3,l6a,17a-triol-20-one is obtained.

EXAMPLE 39 Acetophenone Derivative 0;f 19-N0r-3-Meth0x'y- 1,3,5 1 0 -Pregrzatriene-16ot,1 7a-Di0l-20-One Following the procedure of Example 31 but substituting an equivalent amount of 19-nor-3-methoxy-1,3,5(

' pregnatriene 1605,17 diol -one for the 19-nor- 1,3,5( 10)-pregnatriene-3,16a,17a-triol20-one, the acetophenone derivative of 19 nor 3-methoXy-1,3,5(10)- pregnatriene-l6a,l7u-diol-20-one is obtained.

EXAMPLE 40 Acetophenone Derivative of 6 a-M ethyl-1 9-N 0r-3- Meth0xy-1,3,5 (10 -Pregnatriene-16 x,1 7 a-Diol-ZO-One Following the procedure of Example 31 but substituting an equivalent amount of 6a-methyl-19-nor-3-methoxy- 1,3,5(10)-pregnatriene-16a,17a-diol-20-one for the 19- nor-1,3,5(l0)-pregnatriene-3,16ot,17ot-triol 2O one, the

'acetophenone derivative of 6a-methyl-19-nor-3-methoxy- 1,3,5( l0)pregnatriene-l6a,17a-diol-20-one is obtained.

EXAMPLE 41 A cetophenone Derivatives of 6 fi-M ethyl-1 9-N 0r-3- Meth0xy-1,3,5 (l 0) -Pregnatriene-1 6 a,1 7 a-Diol-ZO-One Following the procedure of Example 31 but substituting an equivalent amount of 6,8-methyl-19-nor-3-rnethoxy- 1,3,5 (10)-pregnatriene-16a,17a-diol-20-one for the 19- nor-1,3,5(10)-pregnatriene-3,16a,17ot-triol 20 one, the acetophenone derivative of 6 3-rnethyl-19-nor-3-methoxy- 1,3,5( 10) -pregnatriene-16a,17a-diol-20-one is obtained.

This invention may be variously otherwise embodied Within the scope of the appended claims.

16 What is claimed is: 1. A compound of the formula --o P m wherein R is selected from the group consisting of hydro gen and lower alkyl; R is selected from the group consisting of hydrogen and lower alkyl; R is selected from the group consisting of B-hydroxy and fi-acyloxy wherein the acyl radical is from a hydrocarbon carboxylic acid of less than ten carbon atoms; R is hydrogen, and together R" and R' is 01m; P is selected from the group consisting of hydrogen, lower alkyl, halo lower alkyl, monocyclic cycloalkyl, monocyclic cycloalkyl lower alkyl, monocyclic aryl, monocyclic aryl lower alkyl, 'monocyclic heterocyclic and monocyc-lic heterocyclic lower alkyl; Q is selected from the group consisting of lower alkyl, halo lower alkyl, monocycliccycloalkyl, monocyclic cycloalkyl lower alkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyolic heterocyclic and monocyclic heterocylie lower alkyl; and together with the carbon to which they are joined P and Q is selected from the group consisting of monocyclic cycloalkyl and monocyclic heterocyclic.

2. 19 nor 1,3,5 (10)-pregnatriene-3,16a,17a=triol-20- one l6a,l7a-acetonide.

3. 6-(lower alkyl) 19 nor 1,3,5(lO)pregnatriene-3, 16a,17ot-tl10120-01'16 16a,l7a-acetonide.

4. 6 methyl 19 nor-1,3,5(10)-pregnatriene-3,16u, 17a-triol-20-one 16a,17a-acetonide.

5. 19 nor 3(lower alkoxy) 1,3,5(10)pregnatriene- 16a,17a-diol-20-one 16a,17a-acetonide.

6. 19 nor 3 met-hoxy-1,3,5(l0)-pregnatriene-16a, 17a-diol-20-one 16a,17a-acetonide.

7. l9 nor 3-(lower alkoxy)-1,3,5(10)pregnatriene- 16a,17a,20;8-triol-16a,17u-acetonide.

8. l9 nor 3 methoxy-1,3,5(10)-pregnatriene-l6e, l7ot,20}8-triol l6a,l7a-acetonide.

9. 19 nor 3 (lower alkoxy)-1,3,5(l0)-pregnatriene- 16a,17a,20fl-trio1 16a,17a-acetonide 20,8-(lower alkanoate).

10. 19 nor 3 methoxy-1,3,5(10)-pregnatriene-16ot, l7ot,20/3-triol 16a,17a-acetonide ZOfi-acetate.

11. A compound of the formula CHa wherein R is selected from the group consisting of hydrogen and lower alkyl, and R" is selected from the group consisting of hydrogen and lower alkyl.

12. 19 nor 1,3,5(10) pregnatriene 3,16u,17ot-triol- 20-one.

1 13. 19 nor 3 metho3 1,3,5(10)-pregnatriene-16a, 3,200,968 Bernstein at 8 1. Oct. 3, 1961 FOREIGN PATENTS References Cited in the file of this patent 854,343 Great Britain OV- 16, 96

UNITED STATES PATENTS 5 OTHER REFERENCES 2,280,828 Inhofien Apr. 28, 1942 Loewenthal: Tetrahedron, 1959, vol. 6, pp. 281 and 2,753,342 'Djerassi et a1. July 3, 1956 282. 

1. A COMPOUND OF THE DORMULA 